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Biomedical subjects

F F Casanueva

Publications and source records attributed to F F Casanueva.

At least 19 recordsLinked to original sources
PubMed2006

Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female Rat.

Kisspeptins, products of the KiSS-1 gene with ability to bind G protein-coupled receptor 54 (GPR54), have been recently identified as major gatekeepers of reproductive function with ability to potently activate the GnRH/LH axis. Yet, despite the diversity of functional states of the female gonadotropic axis, pharmacological characterization of this effect has been mostly conducted in pubertal animals or adult male rodents, whereas similar studies have not been thoroughly conducted in the adult female. In this work, we evaluated maximal LH and FSH secretory responses to kisspeptin-10, as well as changes in sensitivity and hypothalamic expression of KiSS-1 and GPR54 genes, in different physiological and experimental models in the adult female rat. Kisspeptin-10 (1 nmol, intracerebroventricular) was able to elicit robust LH bursts at all phases of the estrous cycle, with maximal responses at estrus; yet, in diestrus LH, responses to kisspeptin were detected at doses as low as 0.1 pmol. In contrast, high doses of kisspeptin only stimulated FSH secretion at diestrus. Removal of ovarian sex steroids did not blunt the ability of kisspeptin to further elicit stimulated LH and FSH secretion, but restoration of maximal responses required replacement with estradiol and progesterone. Finally, despite suppressed basal levels, LH and FSH secretory responses to kisspeptin were preserved in pregnant and lactating females, although the magnitude of LH bursts and the sensitivity to kisspeptin were much higher in pregnant dams. Interestingly, hypothalamic KiSS-1 gene expression significantly increased during pregnancy, whereas GPR54 mRNA levels remained unaltered. In summary, our current data document for the first time the changes in hypothalamic expression of KiSS-1 system and the gonadotropic effects (maximal responses and sensitivity) of kisspeptin in different functional states of the female reproductive axis. The present data may pose interesting implications in light of the potential therapeutic use of kisspeptin analogs in the pharmacological manipulation of the gonadotropic axis in the female.

Animals↗
PubMed2006

Effects of single or repeated intravenous administration of kisspeptin upon dynamic LH secretion in conscious male rats.

The ability of kisspeptins, ligands of the G protein-coupled receptor 54, to potently elicit LH secretion is now undisputed. Yet, most of the pharmacological characterization of their gonadotropin-releasing effects has been conducted after intracerebral administration. In contrast, the effects of peripheral injection of kisspeptin remains less well defined. In this study, dynamic LH secretory responses to iv administration of kisspeptin-10 in different experimental settings are presented, and compared with those evoked by kisspeptin-52, using a protocol of serial blood sampling in conscious, freely moving male rats. LH responsiveness to peripheral administration of kisspeptin appeared extremely sensitive, as doses as low as 0.3 nmol/kg (0.1 microg/rat) evoked robust LH bursts, the magnitude of which was dose-dependent and apparently maximal in response to 3.0 and 30 nmol/kg kisspeptin-10. The ability of kisspeptin-10 to stimulate LH release was fully preserved, and even doubled in terms of relative increases, after short-term fasting despite suppression of prevailing LH levels. Repeated injections of kisspeptin-10 (four boluses, at 75-min intervals) evoked associated LH secretory pulses, the magnitude of which remained constant along the study period. Moreover, in this setting, in vivo LH responses to a terminal injection of GnRH were preserved, whereas basal and depolarization-induced GnRH release ex vivo was significantly enhanced. Finally, iv administration of kisspeptin-52 elicited dynamic LH responses analogous to that of kisspeptin-10; yet, their net magnitude and duration was slightly greater. In summary, we present in this study a series of experiments on the effects of systemic (iv) injection of single or repeated doses of kisspeptin upon dynamic LH secretion in conscious male rats. Aside from potential physiologic relevance, our present data might contribute to setting the basis for the rational therapeutic use of kisspeptin analogs in the pharmacological manipulation of the gonadotropic axis.

Animals↗
PubMed2006

Ghrelin has partial or no effect on appetite, growth hormone, prolactin, and cortisol release in patients with anorexia nervosa.

CONTEXT: Anorexia nervosa (AN) is an eating disorder characterized by self-induced starvation. Gastric hormone ghrelin, potent orexigen, and natural GH secretagogue are increased in AN. Although exogenous ghrelin stimulates appetite, GH, prolactin, and cortisol release in humans, its effects have not been studied, during infusions, in AN patients. OBJECTIVE: The objective of the study was to determine the effects of ghrelin on appetite, sleepiness, and neuroendocrine responses in AN patients. DESIGN: This was an acute interventional study. SETTING: The study was based at a hospital. Investigated SUBJECTS: Twenty-five young women, including nine patients diagnosed with AN with very low body weight, six AN patients who partially recovered their body weight but were still amenorrheic, and 10 constitutionally thin female subjects, without history of eating disorder, weight loss, with regular menstrual cycles, were included in the study. INTERVENTION: Each patient received 300-min iv infusion of ghrelin 5 pmol/kg.min and was asked to complete Visual Analog Scale questionnaires hourly. MAIN OUTCOME MEASURES: Visual Analog Scale scores for appetite and sleepiness, GH, prolactin, and cortisol responses were measured. RESULTS: At baseline, AN patients had significantly higher ghrelin, GH, and cortisol levels and significantly lower leptin than constitutionally thin subjects. GH responses to ghrelin infusion were blunted in patients with AN. Ghrelin administration did not significantly affect appetite but tended to increase sleepiness in AN patients. CONCLUSIONS: Ghrelin is unlikely to be effective as a single appetite stimulatory treatment for patients with AN. Our results suggest that AN patients are less sensitive to ghrelin in terms of GH response and appetite than healthy controls. Ghrelin effects on sleep need further studies.

Adult↗
PubMed2006

Central obestatin administration does not modify either spontaneous or ghrelin-induced food intake in rats.

The isolation of ghrelin unveiled a new system implicated in food intake regulation. The recently isolated hormone obestatin derives from the same precursor of ghrelin and seems to perform opposite actions. It could be part of a dual system connecting gut and brain to regulate energy homeostasis. The ability of intracerebroventricular administration of obestatin to modify food intake was evaluated. Obestatin had no effect on spontaneous food intake in both ad libitum and food restricted rats. The obestatin injection was not able to antagonize the ghrelin-stimulated increase in food intake either. In conclusion, the present work does not support a role for obestatin on the regulation of food intake in any model studied.

Animals↗
PubMed2006

The importance of investigation of pituitary function in children and adolescents following traumatic brain injury.

It is now widely accepted that brain injuries are often the cause of acquired hypopituitarism in adulthood. The information about the pituitary function in brain-injured children and adolescence is however scanty. An international workshop entitled "Traumatic brain injury and hypopituitarism" was held on 9-10 April 2006 in Granada, Spain, in order to explore the relatively unknown but potentially important field of investigation, diagnosis and treatment of pituitary deficiency in children and adolescents following traumatic brain injury (TBI). The following conclusions were reached: 1) a prospective pediatric and adolescent study of pituitary function was indicated; 2) close collaboration among neurosurgeons, neurologists, rehabilitation specialists and pediatric endocrinologists, with support from adult endocrinologists, is essential to achieve a coordinated approach to the care of children after TBI; 3) a model of interaction, similar to that now existing with oncologists, needs to be established; 4) a "pediatric TBI late-effects" service should be created, preferably led by endocrinologists, so that knowledge of growth and puberty can be included, in order to optimize identification, investigation and treatment of this important group of patients.

Brain Injuries↗
PubMed2006

Plasma ghrelin levels of gastrectomized and vagotomized patients are not affected by glucose administration.

BACKGROUND: Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities, secreted mainly by the stomach. Circulating ghrelin concentrations fall rapidly after nutrient ingestion as well as after oral and intravenous glucose challenge. A number of gut hormones including ghrelin require an intact vagal system, which has been hypothesized to have a major role in initiating the postprandial fall in ghrelin levels. AIM: We aimed to investigate the effect of oral glucose challenge on ghrelin secretion in gastrectomized (GASTRX) and vagotomized patients. DESIGN: Interventional study. PATIENTS: Six GASTRX-vagotomized patients and 11 healthy sex- and body mass index (BMI)-matched subjects. METHODS: An oral glucose tolerance test (OGTT) was performed in all subjects. At baseline, circulating plasma total ghrelin, serum glucose, insulin and GH levels were measured. Serum glucose, insulin, GH and plasma ghrelin levels were determined every 30 min for 2 h. RESULTS: Plasma ghrelin levels at baseline were reduced by 55% in GASTRX-vagotomized patients compared to the control group (P < 0.01). In control subjects, plasma ghrelin levels decreased significantly during the OGTT whereas in GASTRX-vagotomized patients no reduction was registered (26.4 +/- 2.8% vs. 5.5 +/- 3.4%). The OGTT revealed a significantly greater increase in circulating glucose levels and serum insulin levels while GH response was not different in GASTRX-vagotomized patients compared to control subjects. CONCLUSIONS: Our data show that circulating ghrelin levels in GASTRX and vagotomized patients were not suppressed after oral glucose administration, unlike control subjects, suggesting that this effect could be due, at least in part, to the lack of contribution of the vagal nervous system to the regulation of ghrelin.

Adult↗
PubMed2006

Effect of acute ghrelin administration on glycaemia and insulin levels in obese patients.

OBJECTIVES: Ghrelin is a 28-amino-acid peptide, predominantly produced by the stomach. There are several studies that suggest the importance of ghrelin in obesity. However, the pancreatic endocrine response to ghrelin in obesity is unclear at present. The aim of this study was to clarify whether ghrelin administration influences glucose and insulin levels in obese patients. PATIENTS AND METHODS: Six obese female patients (31 +/- 3.4 year) with a BMI of 36.1 +/- 7.7 kg/m(2) were studied. Three tests were done: placebo, ghrelin (1 microg/kg, intravenously) and growth hormone-releasing hormone (GHRH; 1 microg/kg, iv) plus ghrelin (1 microg/kg, iv). Blood samples were taken at appropriate intervals for determination of glucose and insulin. Statistical analyses were performed by Wilcoxon and Mann-Whitney tests. RESULTS: Glucose (mean peak, mmol/l) level after placebo administration was 4.9 +/- 0.2. Glucose level after the administration of ghrelin was 5.1 +/- 0.2, not significantly different from the response after placebo (p = NS). Glucose level after the administration of ghrelin plus GHRH was 5.1 +/- 0.2, not significantly different from placebo (p = NS). Insulin (mean peak, mU/l) level after placebo administration was 16.1 +/- 6.1. Insulin level after the administration of ghrelin was 12.3 +/- 1.6, not significantly different from placebo (p = NS). Insulin level after the administration of ghrelin plus GHRH was 11.1 +/- 2.7, not significantly different from the response after placebo (p = NS). CONCLUSIONS: In female obese patients, we did not find significant differences in glucose or insulin levels following ghrelin or GHRH plus ghrelin administration.

Adult↗
PubMed2005

Consensus guidelines on screening for hypopituitarism following traumatic brain injury.

PRIMARY OBJECTIVE: The goal of this consensus statement is to increase awareness among endocrinologists and physicians treating patients with traumatic brain injury (TBI) of the incidence and risks of hypopituitarism among patients with TBI. RATIONALE: TBI poses significant risk to the pituitary gland, leading to elevated risks of diabetes, hypopituitarism and other endocrinopathies. Signs and symptoms associated with hypopituitarism often mimic the sequellae of TBI, although the severity of symptoms is not necessarily related to the severity of the injury. Patients with TBI-induced hypopituitarism may benefit both physically and psychologically from appropriate hormone replacement therapy (HRT). Participants at this unique consensus meeting attempted to define and spearhead an approach to increase awareness of the risks of TBI-induced endocrinopathies, in particular growth hormone deficiency (GHD), and to outline necessary and practical objectives for managing this condition. RECOMMENDATIONS: Systematic screening of pituitary function is recommended for all patients with moderate-to-severe TBI at risk of developing pituitary deficits. Patients with hypopituitarism benefit from appropriate hormonal replacement and prospects for rehabilitation of patients with TBI-induced hypopituitarism may be enhanced by appropriate HRT. Further exploration of this possibility requires: (1) active collaboration between divisions of endocrinology and rehabilitation at the local level to perform a screening of pituitary function in patients after TBI, (2) creation of a consultancy service by endocrine societies for use by rehabilitation centres, (3) development of continuing medical education (CME) programmes that can be offered as crossover training to the physicians who manage the care of patients with TBIs, (4) targeting of patient organizations with educational information for dissemination to patients and their families, (5) continued efforts to more clearly define the population at greatest risk of TBI-induced hypopituitarism and (6) monitor results of efficacy studies as they become available to evaluate whether and how much replacement therapy can improve the symptoms of individuals with TBI-induced hypopituitarism.

Brain Injuries↗
PubMed2005

Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition.

Activation of the gonadotropic axis critically depends on sufficient body energy stores, and conditions of negative energy balance result in lack of puberty onset and reproductive failure. Recently, KiSS-1 gene-derived kisspeptin, signaling through the G protein-coupled receptor 54 (GPR54), has been proven as a pivotal regulator in the control of gonadotropin secretion and puberty. However, the impact of body energy status upon hypothalamic expression and function of this system remains unexplored. In this work, we evaluated the expression of KiSS-1 and GPR54 genes at the hypothalamus as well as the ability of kisspeptin-10 to elicit GnRH and LH secretion in prepubertal rats under short-term fasting. In addition, we monitored the actions of kisspeptin on food intake and the effects of its chronic administration upon puberty onset in undernutrition. Food deprivation induced a concomitant decrease in hypothalamic KiSS-1 and increase in GPR54 mRNA levels in prepubertal rats. In addition, LH responses to kisspeptin in vivo were enhanced, and its GnRH secretagogue action in vitro was sensitized, under fasting conditions. Central kisspeptin administration failed to change food intake patterns in animals fed ad libitum or after a 12-h fast. However, chronic treatment with kisspeptin was able to restore vaginal opening (in approximately 60%) and to elicit gonadotropin and estrogen responses in a model of undernutrition. In summary, our data are the first to show an interaction between energy status and the hypothalamic KiSS-1 system, which may constitute a target for disruption (and eventual therapeutic intervention) of pubertal development in conditions of negative energy balance.

Animals↗
PubMed2005

Effects of chronic hyperghrelinemia on puberty onset and pregnancy outcome in the rat.

Ghrelin, the endogenous ligand of the GH secretagogue receptor, has been recently involved in a wide array of biological functions, including signaling of energy insufficiency and energy homeostasis. On the basis of the proven reproductive effects of other regulators of energy balance, such as the adipocyte-derived hormone leptin, we hypothesized that systemic ghrelin may participate in the control of key aspects of reproductive function. To test this hypothesis, the effects of daily treatment with ghrelin were assessed in rats, pair-fed with control animals, in two relevant reproductive states, puberty and gestation, which are highly dependent on proper energy stores. Daily sc injection of ghrelin (0.5 nmol/12 h; between postnatal d 33 and 43) significantly decreased serum LH and testosterone levels and partially prevented balano-preputial separation (as an external index of puberty onset) in pubertal male rats. On the contrary, chronic administration of ghrelin to prepubertal females, between postnatal d 23 and 33, failed to induce major changes in serum levels of gonadotropins and estradiol, nor did it modify the timing of puberty, as estimated by the ages at vaginal opening and first estrus. Moreover, females treated with ghrelin at puberty subsequently displayed normal estrous cyclicity and were fertile. Conversely, ghrelin administration (0.5 nmol/12 h) during the first half of pregnancy (d 1-11) resulted in a significant decrease in pregnancy outcome, as estimated by the number of pups born per litter, without changes in the number of successful pregnancies at term or gestational length. Overall, our data indicate that persistently elevated ghrelin levels, as a putative signal for energy insufficiency, may operate as a negative modifier of key reproductive states, such as pregnancy and (male) puberty onset.

Animals↗
PubMed2005

Hypopituitarism following traumatic brain injury.

Recent studies have demonstrated that hypopituitarism, and in particular growth hormone (GH) deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or years following head trauma. In addition, it has been shown that post-traumatic neuroendocrine abnormalities occur early and with high frequency. These findings may have significant implications for the recovery and rehabilitation of patients with TBI. Although data emerging after 2000 demonstrate the relevance of the problem, in general there is a lack of awareness in the medical community about the incidence and clinical repercussions of the pathology. Most, but not all, head trauma associated with hypopituitarism is the result of motor accidents. The subjects at risk are those who have suffered moderate-to severe head trauma although mild intensity trauma may precede hypopituitarism also. Particular attention should be paid to this problem in children and adolescents. Onset of pituitary deficits can evolve over years following injury. For the assessment of the GH-IGF axis in TBI patients, plasma IGF-I concentrations, plus dynamic GH testing is indicated. Some degree of hypopituitarism is found in 35-40% of TBI patients. Among multiple pituitary deficits, the most common ones were GHD and gonadotrophin deficiency. In most series 10-15% presented with severe GHD and 15% with partial GHD after stimulating GH secretion confirming that the most common isolated deficit is GHD. Psychometric evaluation together with neurocognitive testing shows variability of disability and the possibility that untreated TBI induced hypopituitarism contributes to the chronic neurobehavioral problems seen in many head-injured patients warrants consideration. Preliminary data, from small pilot, open-label studies show that subjects treated with GH experience significant improvements in concentration, memory, depression, anxiety and fatigue. In conclusion, pituitary failure can occur even in minor head injuries and is poorly recognized.

Brain Injuries↗
PubMed2005

Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat.

KiSS-1 was originally identified as a metastasis suppressor gene encoding an array of structurally related peptides, namely kisspeptins, which acting through the G protein-coupled receptor GPR54 are able to inhibit tumor progression. Unexpectedly, a reproductive facet of this newly discovered system has recently arisen, and characterization of the role of the KiSS-1/GPR54 system in the neuroendocrine control of gonadotropin secretion has been initiated. However, such studies have been so far mostly restricted to LH, and very little is known about the actual contribution of this system in the regulation of FSH release. To address this issue, the effects of KiSS-1 peptide on FSH secretion were monitored in vivo and in vitro under different experimental conditions. Intracerebroventricular administration of KiSS-1 peptide significantly stimulated FSH secretion in prepubertal and adult rats. Yet, dose-response analyses in vivo demonstrated an ED(50) value for the FSH-releasing effects of KiSS-1 of 400 pmol, i.e. approximately 100-fold higher than that of LH. In addition, systemic (ip and iv) injection of KiSS-1 significantly stimulated FSH secretion in vivo. However, KiSS-1 failed to elicit basal FSH release directly at the pituitary level, although it moderately enhanced GnRH-stimulated FSH secretion in vitro. Finally, mechanistic studies revealed that the ability of KiSS-1 to elicit FSH secretion was abolished by the blockade of endogenous GnRH actions, but it was persistently observed in different models of leptin insufficiency and after blockade of endogenous excitatory amino acid and nitric oxide pathways, i.e. relevant signals in the neuroendocrine control of gonadotropin secretion. In summary, our results extend previous recent observations on the role of KiSS-1 in the control of LH secretion and provide solid evidence for a stimulatory effect of KiSS-1 on FSH release, acting at central level. Overall, it is proposed that the KiSS-1/GPR54 system is a novel, pivotal downstream element in the neuroendocrine network governing gonadotropin secretion.

Animals↗
PubMed2005

Genetic basis of short stature.

Growth in humans is a complex process controlled by many genetic and non-genetic factors. It is influenced by endogenous factors like genetics, hormones and metabolism as well as exogenous ones like nutrition, physical activity and psychosocial status. Growth is one of the most sensitive markers of children's health, their nutritional status and genetic background. Besides, deviation from normality may be the first manifestation of an underlying congenital or acquired pathology. Thus, it is important to know the growth process and the disorder that can disturb it. Short stature is defined as a condition in which the height of an individual is more than 2 SD below the corresponding mean height for a given age, sex and population group. This disorder is a major concern for patients and their parents, and represents a diagnostic challenge to the clinician. A correct diagnosis is particularly important in view of the availability of effective, but costly, therapy in a small subset of cases. Cytogenetic and molecular analysis can be of great value in this diagnostic process. Emphasis can be made on the advances of molecular genetics, which have characterized human genes involved in the hypothalamus-pituitary-GH axis such as GH, POU1F1, PROP1, GHRHR, GHR, IGF, IGFR, HESX1, LHX3, LHX4, among others. Our current line of investigation is related to the study of some of these genes and the genotype-phenotype relation with the aim of identifying features that add some more light on the genetic origins of short stature.

Base Sequence↗
PubMed2005

Hypopituitarism following traumatic brain injury (TBI): call for attention.

Recent studies have demonstrated that hypopituitarism, in particular GH deficiency, is common among survivors of traumatic brain injury (TBI) years tested several months or following head trauma. In addition, it has been shown that post-traumatic neuroendocrine abnormalities occur early and with high frequency. These findings may have significant implications for the recovery and rehabilitation of patients with TBI. Although data emerging after year 2000 demonstrate the relevance of the problem, in general there is a lack of awareness in the medical community about the incidence and clinical repercussions of the pathology. Most, but not all, head trauma associated with hypopituitarism is the result of motor vechicle accidents. The subjects at risk are those who have suffered moderate-to-severe head trauma, although mild intensity trauma may also precede hypopituitarism. Particular attention should be paid to this problem in children and adolescents; onset of pituitary deficits can evolve over years following injury. Plasma IGF-I concentrations, plus dynamic GH testing, are indicated for the assessment of the GH-IGF axis in TBI patients. Some degree of hypopituitarism is found in 35-40% of TBI patients. Among mulitple pituitary deficits, the most common ones were GH deficiency (GHD) and gonadotrophin deficiency. In most series, 12-15% presented with severe GHD and 14% with partial GHD after stimulating GH secretion, confirming that the most common isolated deficit is GHD. Psychometric evaluation and neurocognitive testing show variability of disability, and these measures are needed and important to support hormonal replacement. Preliminary data, from small pilot, open-label studies show that subjects treated with GH experience significant improvements in concentration, memory, depression, anxiety and fatigue. In conclusion, pituitary failure can occur even in minor head injuries and is poorly recognized.

Brain Injuries↗
PubMed2005

Can treatment with somatostatin analogs replace neurosurgery?

There is an ongoing controversy on first-line treatment in acromegaly. Although transsphenoidal surgery has always traditionally been considered the first option, the evolution of new medical treatments is now challenging the clinical paradigm. In fact, somatostatin analogs are highly effective, convenient, avoid the growth of tumors or even shrink them, and also have the advantage of preserving normal pituitary function. On the other hand, when successful, neurosurgery has the advantage of eliminating long-term medical treatment and is less expensive. This manuscript discusses the pros and cons of both treatments.

Acromegaly↗
PubMed2004

Expression of growth hormone secretagogue receptor type 1a, the functional ghrelin receptor, in human ovarian surface epithelium, mullerian duct derivatives, and ovarian tumors.

Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R), is a newly identified, ubiquitously expressed molecule that has been involved in a wide array of endocrine and nonendocrine functions, including cell proliferation. In this context, our group recently reported the expression of ghrelin and its functional receptor, the GHS-R type 1a, in the human ovary and testis as well as several testicular tumors. Ovarian malignancies, however, remain unexplored. Notably, a vast majority of ovarian tumors derive from the surface epithelium, which originates from the celomic epithelium. Considering the proven expression of ghrelin in the human ovary, and its reported effects in the proliferative activity of different cancer cell lines, we aimed at evaluating whether the ovarian surface epithelium as well as related reproductive structures and tumors are potential targets of ghrelin. To this end, expression of GHS-R1a was analyzed by immunohistochemistry in a panel of normal, metaplastic, and neoplastic tissues. Uniform GHS-R1a immunostaining was detected throughout the ovarian surface epithelium. Likewise, ciliated cells within the fallopian tube epithelium showed strong GHS-R1a expression. In contrast, other celomic derivatives, such as endometrium and endocervix, were negative for GHS-R1a immunoreactivity. In keeping with data from normal tissues, inclusion cysts from the surface epithelium expressed GHS-R1a. Similarly, benign serous tumors resembling fallopian tube epithelium were also positive, whereas serous cystadenocarcinomas showed GHS-R1a expression only in highly differentiated specimens. In contrast, other neoplasms, such as mucinous cystadenomas and cystadenocarcinomas, endometrioid tumors, clear cell carcinomas, and Brenner tumors, did not express GHS-R1a. In conclusion, our results demonstrate that the ovarian surface epithelium and related tumors are potential targets for systemic or locally produced ghrelin because they express the functional type 1a GHS-R. Considering the relevant role of the ovarian surface epithelium in key physiological events (such as ovulation) and neoplastic transformation of the ovary, the potential actions of ghrelin in those phenomena merit further investigation.

Cervix Uteri↗
PubMed2004

The endogenous growth hormone secretagogue (ghrelin) is synthesized and secreted by chondrocytes.

Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHS-R), is a recently isolated hormone, prevalently expressed in stomach but also in other tissues such as hypothalamus and placenta. This novel acylated peptide acts at a central level to stimulate GH secretion and, notably, to regulate food intake. However, the existence of further, as yet unknown, effects or presence of ghrelin in peripheral tissues cannot be ruled out. In this report, we provide clear evidence for the expression of ghrelin peptide and mRNA in human, mouse, and rat chondrocytes. Immunoreactive ghrelin was identified by immunohistochemistry in rat cartilage, being localized prevalently in proliferative and maturative zone of the epiphyseal growth plate, and in mouse and human chondrocytic cell lines. Moreover, ghrelin mRNA was detected by RT-PCR and confirmed by Southern analysis in rat cartilage as well as in mouse and human chondrocytes cell lines. Ghrelin mRNA expression has been studied in rat along early life development showing a stable profile of expression throughout. Although ghrelin expression in chondrocytes suggests the presence of an unexpected autocrine/paracrine pathway, we failed to identify the functional GH secretagogue receptor type 1A by RT-PCR. On the other hand, binding analysis with 125I ghrelin suggests the presence of specific receptors different from the 1A isotype. Scatchard analysis revealed the presence of two receptors with respectively high and low affinity. Finally, ghrelin, in vitro, was able to significantly stimulate cAMP production and inhibits chondrocytes metabolic activity both in human and murine chondrocytes. In addition, ghrelin is able to actively decrease both spontaneous or insulin-induced long chain fatty acid uptake in human and mouse chondrocytes. This study is the first to provide evidence for the presence of this novel peptide in chondrocytes and suggests novel potential roles for this newly recognized component of the GH axis in cartilage metabolism.

Animals↗